The Role of the Cardiomyocyte HIF pathway and FOG2 in Coronary Microvascular Disease

心肌细胞HIF通路和FOG2在冠状动脉微血管疾病中的作用

• 批准号: 9897548
• 负责人: Marie A Guerraty
• 金额: $ 16.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897548
• 关键词: Academic Medical Centers; Achievement; Address; Adult; Advisory Committees; Affect; Anaerobic Bacteria; Angiogenic Factor; Award; Biological Markers; Blood capillaries; Blood flow; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Culture Techniques; Cell Respiration; Cells; Coronary; Coronary Arteriosclerosis; Coronary heart disease; DNA; Data; Development; Diabetic mouse; Disease; EFRAC; Environment; Fatty Acids; Friends; Functional Imaging; Functional disorder; GATA4 gene; Genetic; Goals; Health Care Costs; Heart; Heart Diseases; Heart failure; Histologic; Human; Hypoxia; Hypoxia Inducible Factor; Immune; In Vitro; Infiltration; Ischemia; Knockout Mice; Maintenance; Mediating; Medicine; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Microvascular Dysfunction; Mitochondria; Morbidity - disease rate; Mus; Myocardial; Myocardial perfusion; Myocardial tissue; Pathology; Pathway interactions; Patients; Perfusion; Phenotype; Physicians; Plasma; Play; Procollagen-Proline Dioxygenase; Research; Research Proposals; Role; Scientist; Signal Transduction; Structure; Therapeutic; Tissue Sample; Transcription Coactivator; Up-Regulation; VEGFA gene; adeno-associated viral vector; angiogenesis; arteriole; base; biobank; career; cohort; conditional knockout; density; direct application; evidence base; experimental study; genetic variant; glucose metabolism; heart metabolism; improved; in vivo; innovation; mortality; mouse model; novel; novel therapeutics; preservation; programs; response; targeted treatment; therapeutic target; transcription factor

PROJECT SUMMARY Coronary microvascular disease (CMVD), or disease of the coronary pre-arterioles, arterioles, and capillaries, has become an increasingly well-recognized cardiac pathology, which carries a high burden of morbidity, healthcare costs, and increased mortality. CMVD exists in isolation and also exacerbates other cardiac disease such as coronary artery disease (CAD) and cardiomyopathies. In addition, the pathophysiology of CMVD also has implications for heart failure with preserved ejection fraction (HFpEF) and coronary collateral formation. The Hypoxia-Inducible Factor 1a (HIF) pathway is activated in response to hypoxia and has been studied in the context of coronary microvasculature and cardiac perfusion. Signaling through the HIF pathway promotes angiogenesis and may improve microvascular structure, however, the HIF pathway is known to have deleterious metabolic effects on cardiomyocytes. Uncoupling the beneficial angiogenic and deleterious metabolic effects of the HIF pathways would therefore be highly beneficial. Evidence that FOG2, a transcriptional co-activator of GATA4, is a key regulator of coronary development and the maintenance of coronary microvasculature into adulthood, have led to the novel hypothesis that FOG2 is a critical regulator in the HIF pathway and that FOG2 can mediate HIF-induced coronary angiogenesis without deleterious effects on cardiac metabolism. I have developed a translational framework consisting of 1) a mouse model of CMVD and 2) functional imaging of the mouse coronary microvasculature to help investigate this hypothesis. Three interrelated Specific Aims will address the hypothesis: 1) Characterize HIF-induced angiogenesis and metabolic changes in cardiomyocytes and determine whether FOG2 mediates HIF induction of angiogenic and metabolic pathways in cardiomyocyte cell culture; 2) Delineate the role of HIF and FOG2 pathways in CMVD and determine whether FOG2 mediates HIF induction of coronary angiogenesis without affecting cardiac metabolism in mice; and 3) Define the role of the HIF and FOG2 pathways in CMVD in humans. The experiments in this innovative proposal will also have direct application toward the development of novel therapies for CMVD. In addition, the research proposal is supported in an integrated manner through exceptional mentorship, a research advisory committee filled with relevant expertise, and unequivocal divisional and institutional commitment. Finally, this K08 award will serve as a basis for the achievement of my ultimate career goal to become an independent physician-scientist at a major academic medical center.

项目概要 冠状动脉微血管疾病（CMVD），或冠状动脉前小动脉、小动脉和毛细血管疾病， 已成为一种日益得到广泛认可的心脏病理学，其发病率很高， 医疗费用和死亡率增加。 CMVD 单独存在，也会加剧其他心脏病 例如冠状动脉疾病（CAD）和心肌病。此外，CMVD 的病理生理学还 对射血分数保留的心力衰竭（HFpEF）和冠状动脉侧支形成具有影响。 缺氧诱导因子 1a (HIF) 通路在缺氧时被激活，并已在以下领域进行了研究： 冠状动脉微血管和心脏灌注的背景。通过 HIF 通路的信号传导促进 血管生成并可能改善微血管结构，然而，已知 HIF 途径具有 对心肌细胞的有害代谢作用。解开有益的血管生成和有害的血管生成 因此，HIF 途径的代谢作用将是非常有益的。有证据表明 FOG2 GATA4 的转录共激活因子，是冠状动脉发育和维持的关键调节因子 冠状动脉微血管进入成年期，导致了新的假设：FOG2 是一个关键的调节因子 FOG2 可以介导 HIF 诱导的冠状动脉血管生成，且不会产生有害影响 对心脏代谢的影响。我开发了一个翻译框架，其中包括 1) 小鼠模型 CMVD 的研究和 2) 小鼠冠状动脉微血管的功能成像有助于研究这一假设。 三个相互关联的具体目标将解决这一假设：1) 表征 HIF 诱导的血管生成和 心肌细胞的代谢变化并确定 FOG2 是否介导 HIF 诱导血管生成和 心肌细胞培养中的代谢途径； 2) 描述 HIF 和 FOG2 通路在 CMVD 中的作用 并确定 FOG2 是否介导 HIF 诱导冠状动脉血管生成而不影响心脏 小鼠的新陈代谢； 3) 定义 HIF 和 FOG2 通路在人类 CMVD 中的作用。这 这项创新提案中的实验也将直接应用于新型药物的开发 CMVD 的治疗。此外，该研究提案通过以下方式得到综合支持： 卓越的指导、充满相关专业知识的研究咨询委员会以及明确的 部门和机构承诺。最后，这个K08奖将作为我取得成就的基础 最终职业目标是成为主要学术医疗中心的独立医师科学家。